The role of RTK signaling in opioid tolerance

描述(由申请者提供)：据估计，超过1亿美国人患有慢性疼痛，每年给我们的社会造成超过5000亿美元的损失。几个世纪以来，吗啡等阿片类药物一直是治疗剧烈疼痛的一线药物。然而，随着时间的推移，对阿片类药物的止痛会产生耐受性。当阿片类药物无效时，患者面临更高的风险和痛苦。在这项提案中，我描述了我们的突破性发现：临床使用的表皮生长因子受体(EGFR；ErbB1)拮抗剂吉非替尼(Iressa)完全逆转了吗啡耐受。根据我们的发现，我们假设：1)ErbB信号是引起吗啡耐受的必要条件和充分条件；2)长期阿片给药增加ErbB信号并可能导致不完全交叉耐受现象；3)慢性阿片给药不同地调节ErbB在背根节和胶状质的表达和共存；以及4)阿片类药物诱导的ErbB信号输出由严格调控的转录网络决定。我们将通过以下具体目标的研究来验证这些假说：1)确定ErbB受体信号介导阿片耐受的机制；2)确定阿片耐受对ErbB信号的影响以及ErbB信号是否可以解释不完全交叉耐受；3)定义在脊髓背根神经节和背角表达ErbB受体的特定细胞亚型，并确定它们的解剖关系是否因长期服用阿片而改变；4)确定阿片类药物诱导的ErbB信号反应的调节，并开始定义这些反应背后的网络结构。这些研究将极大地提高我们对阿片类药物耐受的分子机制的理解。它们还可能导致一种治疗慢性疼痛的全新方法。我们的发现有可能极大地减少人类的痛苦，并提高数百万患有顽固性疼痛的患者的生活质量。

DESCRIPTION (provided by applicant): It is estimated that over 100 million Americans suffer from chronic pain at an annual cost to our society of over 500 billion dollars. For centuries, opioid drugs such as morphine have been the first-line treatment for severe pain. However, over time tolerance to opioid analgesia develops. Patients face increased risk as well as suffering when opioids lose effectiveness. In this proposal I describe our groundbreaking discovery that the clinically used epidermal growth factor receptor (EGFR; ErbB1) antagonist gefitinib (Iressa) completely reverses morphine tolerance. Based on our findings, we hypothesize that: 1) ErbB signaling is necessary and sufficient to cause morphine tolerance; 2) Chronic opioid administration increases ErbB signaling and may underlie the phenomenon of incomplete cross tolerance; 3) Chronic opioid administration differentially regulates ErbB expression and co-localization in the dorsal root ganglion and substantia gelatinosa; and 4) Opioid-induced ErbB signaling outputs are determined by a tightly regulated transcriptional network. We will test these hypotheses by performing studies with the following Specific Aims: 1) Define the mechanisms by which ErbB receptor signaling mediates opioid tolerance; 2) Determine the effects of opioid tolerance on ErbB signaling and whether ErbB signaling can explain incomplete cross tolerance; 3) Define the specific cellular subtypes expressing ErbB receptors in the dorsal root ganglion and dorsal horn of the spinal cord, and determine if their anatomic relationships are altered by chronic opioid administration; and 4) Determine the regulation of ErbB signaling responses induced by opioids, and begin to define the network structure that underlies these responses. These studies should dramatically improve our understanding of the molecular mechanisms underlying opioid tolerance. They also may lead to a completely new approach for the treatment of chronic pain. Our findings have the potential to dramatically reduce human suffering and improve the quality of life for untold millions of patients suffering from intractable pain.